Patent GB-550262-A (GB)
Title: Synthesis of ketones having a diethylstilboestrol carbon skeleton
IPC: C07C39/215
Filed: 1941-07-25
Abstract: 550,262. Ketones related to diethylstilboestrol. WELLCOME FOUNDATION, Ltd., BROWNLEE, G., and DUFFIN. W. M. July 25,1941, Nos. 9434 and 14147. [Class 2 (iii)] Ketones having a diethyl-stilboestrol or an α:α<SP>1</SP>-diethyl -dibenzyl carbon skeleton are prepared by reacting a compound having the above carbon skeleton with an aliphatic acid, acid anhydride, or acid halide under acylating conditions so that one or more -CO.R groups (where R is alkyl or substituted alkyl) are introduced into one or both of the benzene rings. The reaction is preferably carried out by means of the Friedel-Crafts or similar reaction by heating the starting material and an acid, acid anhydride, or acid halide with anhydrous aluminium, zinc, antimony, cadmium or ferric chlorides or aluminium bromide, or by heating aliphatic esters of phenols having the above carbon skeleton with aluminium chloride, zinc chloride or like condensing agents whereby the acyl group or groups are displaced from the phenolic hydroxyl group into the aromatic ring. The esters in the latter case need not be preformed, the phenol, condensing agent and acylating agent may be simply'heated together. When starting materials with more than one hydroxyl group are employed it is possible to esterify one or more of such group simultaneously with the introduction of one or more ketone groups elsewhere in the molecule. Substituted acylating agents may be used leading to the formation of substituted -CO.R groups. In particular the use of chloracetyl chloride leads to the introduction of the -CO.CH 2 Cl group, and acetyl-glycollyl chloride leads to the introduction of the CO.CH 2 OH group. The halogen substituted ketones may either be reduced to give unsaturated ketones or hydrolysed to give ketones having a hydroxyl substituent. The reduction may be carried out in the presence of a palladiumcharcoal catalyst, and the hydrolysis by means of alcoholic potash. The isolation of the ketones is preferably accomplished by the use of Girard's reagents. In examples (1) p -methoxy -x α<SP>1</SP>- diethyldibenzyl is reacted with acetic anhydride in nitrobenzene in the presence of aluminium chloride to give 4 -methoxy -4<SP>1</SP> -acetyl -a α<SP>1</SP>- diethyldibenzyl. (2) p-Methoxy - α α<SP>1</SP> - diethyldibenzyl is reacted with acetyl chloride in carbon disulphide in the presence of aluminium chloride to give the same product as obtained in example (1). (3) Diethylstilboestrol diacetate is heated with anhydrous aluminium chloride at 140‹C. to give 4 : 4<SP>1</SP> -dihydroxy - diacetyl - α α<SP>1</SP> -diethylstilbene. (4) Diethylstilboestrol monoethyl ether is treated with acetyl chloride in the presence of anhydrous zinc chloride to give 4 -methoxy -41 -hydroxy - 3<SP>1</SP> =acetyl - α α<SP>1</SP>- diethylstilbene. (5) p- Methoxy - α α<SP>1</SP> -diethyldibenzyl is treated with monochloroacetyl chloride in carbon disulphide in the presence of aluminium chloride to give 4 - methoxy - 41 -monochloracetyl α - α<SP>1</SP> -diethyldibenzyl. The corresponding di- and trichloroacetyl ketones may be obtained by the use of the di- and trichloroacetyl chlorides. (6) p-Methoxy -α α<SP>1</SP> - diethyldibenzyl is treated with acetylglycollyl chloride in carbon disulphide in the presence of aluminium chloride to give 4 - methoxy - 4<SP>1</SP> - glycollyl -acetyl -α α<SP>1</SP> diethyldibenzyl. (7) The product of example (5) is reduced with hydrogen in the presence of a palladium charcoal catalyst in acetone solution to give a ketone having a progesterone activity. (8) The product of example (5) is saponified with alcoholic potassium hydroxide to give 4 - methoxy - 4'-glycollyl - α α<SP>1</SP> diethyldibenzyl which can be extracted with ether. Acidification of the mother liquor followed by a second extraction with ether yields a white product which like the first product has corticosterone-like activity. (9) 4-Hydroxy -α α<SP>1</SP>- diethyldibenzyl is treated with monochloracetyl chloride in carbon disulphide in the presence of anhydrous aluminium chloride to give 4<SP>1</SP> monochloracetyl - α α<SP>1</SP> diethyldibenzyl-4-monochloracetate.